A hydrogel has been widely studied as a material for pharmaceutical and biomedical applications, e.g., implants, drugs, and cell delivery carriers, based on its biocompatibility, high water contents and excellent permeability of metabolites and nutrients. Such a hydrogel can be prepared using natural and synthetic polymers and formed through a variety of chemical and physical cross-linkages. Over the past decade, the research has been focused on the improvement of an in situ-forming hydrogel prepared by injecting a polymer solution into the body to form a hydrogel in vivo.
Such an in situ-forming hydrogel can be used as an injectable hydrogel system in a living body. The injectable hydrogel system has received a lot of attention due to the ease of application forms to give comfort to a patient, based on minimal invasive techniques.
The injectable hydrogel system refers to an injectable fluid capable of forming a hydrogel in the body before being solidified in a desired tissue, organ, or body cavity, based on minimal invasive techniques.
For example, the injectable hydrogel system can be integrated through a simple mixing of many therapeutic drugs, rather than through surgical procedures for implantation. The injectable hydrogel system enables to fill a defect site or depression in the body cavity. The injectable hydrogel system generally exhibits weak mechanical properties, but has many advantages including high efficiency in cell separation, functions of a carrier for delivering a physiological active substance or a drug, such as a peptide, a protein, and DNA, and excellent transport of nutrients to cells and products.
However, the conventional injectable hydrogels developed by heat-treatment or UV irradiation have several problems in a time-consuming manufacture of a polymer solution, high solution viscosity, and slow phase transition. In order to solve such problems of the conventional in situ-forming hydrogel, an in situ-forming hydrogel using an enzyme reaction has been recently developed.
A recently developed in situ-forming hydrogel is used to develop an in situ-forming hydrogel system through an enzyme oxidation reaction occurring in the presence of horseradish peroxidase (HRP) and hydrogen peroxide (H2O2), and the in situ-forming hydrogel system overcomes disadvantages, e.g., weak mechanical strength and body stability, of the conventional hydrogel that has been prepared through a physical or chemical cross-linking reaction.
Types of an enzyme-sensitive in situ-forming hydrogels that is currently under development are as follows: Tetronic-tyramine (Tet-TA) (Park et al., Biomacromolecules 2010/2012, Soft Matter 2011), gelatin-polyethylene glycol-tyramine (GPT) (Park et al., Journal of Materials Chemistry 2011), dextran-tyramine (dec-TA) (Jin et al., Biomaterials 2007), hyaluronic acid-tyramine (HATA) (Kurisawa et al., Chem. Commun. 2005), gelatin-hydroxypropionic acid (GHPA) (Wang et al., Biomaterials 2009), gelatin-tyramine (GTA) (Sakai et al., Biomaterials 2009), alginate-tyramine (ATA) (Sakai et al., Acta Biomaterialia 2007), etc.
The enzyme-sensitive in situ-forming hydrogel includes a phenol derivative in a polymer chain, and according to a HRP-mediated coupling reaction, the phenol derivative forms a hydrogel through a carbon-carbon bond at the ortho position or a bond between a carbon at the ortho position and an oxygen of phenoxy oxygen. In addition, the enzyme-sensitive in situ-forming hydrogel has physical and chemical properties, e.g., gel formation time, mechanical strength, and biodegradability, that can be easily adjusted by adjusting the concentration of HRP and H2O2, and has advantages that a variety of physiologically active substances, drugs, and cells can be easily deposited in the hydrogel. However, the enzyme-sensitive in situ-forming hydrogel includes enzymes, e.g., HRP derived from animals and plants, formed therein, and thus, in the case of injection into the body, problems related to in vivo safety, e.g., immune responses, may occur.